Live-attenuated SIV vaccines have shown marked efficacy in protecting against virulent viral challenge under a variety of experimental conditions, however, the safety of a live-attenuated vaccine still requires careful study. During the previous granting period experiments were performed that addressed the safety of live-attenuated deletion mutant vaccines in rhesus monkeys (exposure to multiple high doses, oral infection of neonates, infection of pregnant mothers and direct inoculation into the central nervous system) and the efficacy against intravenous, mucosal and heterologous virus challenge. The objectives of the current proposal are 1) to further define safety issues associated with a live-attenuated AIDS vaccines using the SIV model and 2) to develop strategies that accelerate the onset of protection and increase the breadth of protection to heterologous SIV strains and various routes of exposure. In addition, a number of animals from experiments initiated during the previous granting period will be maintained to gather safety data on the long term effects of the live-attenuated vaccines in neonates. To further define safety the proposed experiments will investigate the effect on virus load of immunosuppression at the time of vaccination, of acute and chronic immune stimulation (with soluble antigens, BCG and chronic parasitic infections) and co-infection with SRV-1 and a new herpes virus rhKSHV. The safety of animal to animal passage (reversion to virulence) and the amount of virus in genital secretions (risk of unintended transmission) will also be studied. In the area of efficacy a polyvalent approach with multiple deletion mutant strains will be tested for its ability to broaden the heterologous protection. A time course study to determine the onset of immunity with SIVdelta4 and vaginal challenge and a study to assess protection of SIVdelta3 in the face of cell associated exposure are also proposed.